Pathology of Soft Tissue TumorsRiyam Zreik, MD

Department of Pathology

Email: Riyam.Zreik@BSWHealth.org

Reading

• Robbins and Cotran 9th ed. pp. 1207-1219

• Other Sources

Learning Objectives - Soft tissue tumors

• Describe the more common benign and malignant soft tissue tumors including:• General classification (benign vs malignant)

• Clinical features/presentation

• Radiologic and pathologic findings

• Genetic/molecular findings

• Treatment including targeted therapy

• Prognosis

Soft Tissue Tumors• Adipocytic Tumors

• Lipoma – Benign • Liposarcoma – Malignant

• Fibroblastic/Myofibroblastic Tumors• Nodular Fasciitis• Myositis Ossificans• Desmoid Type Fibromatosis• Dermatofibrosarcoma Protuberans – Malignant

• Fibrohistiocytic Tumors• Tenosynovial giant cell tumor

• localized (giant cell tumor of tendon sheath)• diffuse (PVNS, pigmented villonodular synovitis)

• Smooth Muscle Tumors• Leiomyoma• Leiomyosarcoma

• Skeletal Muscle (striated muscle) Tumors• Rhabdomyosarcoma• Rhabdomyoma (benign) – not discussed

• Vascular Tumors• Hemangioma• Kaposi Sarcoma• Angiosarcoma

• Gastrointestinal stromal tumors

• Nerve Sheath Tumors• Schwannoma• Neurofibroma• Malignant peripheral nerve sheath tumor

• Tumors of Uncertain Differentiation• Synovia l Sarcoma

Adipocytic Tumors

Lipoma

• Benign tumor composed of mature adipocytes

• Most common mesenchymal neoplasm in adults

• Age: 40s-60s

• Site: usually superficial (subcutaneous) or intramuscular

• Can be single or multiple

• Gross: Well-circumscribed, usually <5 cm, fine fibrous bands (trabeculae)

• Treatment: Excision as needed

Lipoma

Liposarcoma

• Malignant adipocytic neoplasm

• Heterogeneous group of tumors• 5 major subtypes:

• 1) atypical lipomatous tumor/well-differentiated liposarcoma

• 2) dedifferentiated liposarcoma

• 3) myxoid/round cell liposarcoma (limbs)

• 4) pleomorphic liposarcoma

• 5) mixed type liposarcoma

• Most common malignant soft tissue tumor

Liposarcoma

• Classification Based on Site: (risk of dedifferentiation)• Atypical lipomatous tumor (ALT) – Limbs

• surgically accessible sites; lower risk of dedifferentiation

• Well Differentiated Liposarcoma – retroperitoneum, mediastinum, spermatic cord • difficult to access sites; increased risk of dedifferentiation

• Presentation depends on location and tumor variant

Liposarcoma

• Age: adults (50-70 years)

• Gross: usually well circumscribed; varying amounts of yellow (fatty) component intermixed with tan thicker fibrous bands

Liposarcoma

• Histology: • Lipoblast – hyperchromatic nucleus with

cytoplasmic vacuole that pushes and indents the nucleus

• Usually composed either entirely or partly of lipoblasts, mature adipocytes, and atypical stromal cells

Lipoblast ALT/well differentiated

Normal mature fat cells

Liposarcoma

• Genetic Findings:• ALT/well differentiated –MDM2 gene amplification

• Dedifferentiated liposarcoma –MDM2 gene amplification

• Myxoid/Round Cell Liposarcoma – t(12;16) FUS-DDIT3 fusion

• Pleomorphic Liposarcoma – complex karyotype aberrations

• Treatment: depends on subtype, chemo/radiation/surgery

• Prognosis: depends on subtype

MDM2 gene amplification

Myxoid/Round Cell Liposarcoma

Fibroblastic/myofibroblastictumors

Nodular Fasciitis

• Self limiting fibrous neoplasm arising in subcutaneous tissue composed of plump uniform (myo)fibroblastic cells with a tissue culture-like growth pattern

• MYH9-USP6 gene fusion

Fibroblast cells in tissue culture Nodular fasciitis

Nodular fasciitis

Nodular Fasciitis

• Sites: upper extremity, trunk, head and neck

• Grows rapidly• 10% have history of trauma

• Excision is curative

• Rapid growth and often numerous mitotic figures -> can be concerning for sarcoma

Myositis ossificans

• Localized self limiting lesion composed of reactive hypercellular fibrous tissue and bone

• Age: usually young adults

• Sex: male predominance

• Injury to soft tissue is the initiating event (60-75% of cases)

Myositis Ossificans

• Radiology and gross/microscopic findings: zonal proliferation• depends on phase of lesion

• Rim of calcifications mature (periphery)

• Central bone is more immature

• Treatment: Excision is curative

Myositis ossificans

Peripheral rim of mature calcifications

Immature bone in the center of the lesion

Hypercellular reactive fibrous tissue

Fibromatoses

Superficial

•Palmar – Dupuytren contracture

•Plantar – Ledderhosedisease

•Penile – peyronie disease

Deep

•Desmoid type fibromatosis

Superficial Fibromatosis

• tends to recur locally

• Palmar – Dupuytren contracture

• Plantar – Ledderhose disease

• Penile – peyronie disease

• Treatment: excision

Desmoid-type Fibromatosis

• locally aggressive (myo)fibroblastic neoplasm

• infiltrative growth

• tends to recur but lacks malignant potential

• CTNNB1 mutations (Beta Catenin)

• Associated with Gardner-type familial adenomatous polyposis (FAP)

Infiltrating skeletal muscle

Desmoid-type Fibromatosis

• Streaming fascicles of bland uniform fibroblasts with no atypia

Infiltrating skeletal muscle

Dermatofibrosarcoma Protuberans (DFSP)

• Malignant

• Superficial, low-grade, locally aggressive fibroblastic neoplasm characterized by COL1A1-PDGFB fusion gene.

• Progression to fibrosarcoma is seen in 10-15% of cases

• Young to middle aged adults with a slight male predominance

Dermatofibrosarcoma Protuberans

• Nodular or multinodular cutaneous mass with slow but persistent growth .

• Early on show plaque-like growth with peripheral red discoloration

• Treatment: wide excision with tumor free margins

• Prognosis: 20-50% recurrence rate (dependent on margins)• Fibrosarcomatous DFSP can recur (20-50%) and

metastasize (13%)

Dermatofibrosarcoma Protuberans

Infiltrating surrounding fat (honeycomb look)

Storiform/whorled growth pattern

Fibrosarcomatous transformation (left)of DFSP (right)

Fascicular growth

Tumors of smooth muscle origin

Leiomyoma

• Benign tumor of smooth muscle origin

• Uterine fibroids are the most frequent leiomyomas and develop in up to 80% of women

• May arise at any site where smooth muscle is present

Cells with cigar-shaped nuclei arranged in fascicles

Uterine Leiomyoma

• Most common tumor in females

• Often presents with multiple discrete tumors

• Estrogen sensitive• Increases in size with pregnancy

• Decreases in size with menopause

• Whorled bundles of smooth muscle

• May cause abnormal uterine bleeding or miscarriage

Leiomyosarcoma

• Malignant neoplasm of smooth muscle origin

• Sites: uterus, retroperitoneum (arises off of large blood vessels), pelvis, and lower extremities

• Treatment: Multimodal

• Prognosis: local recurrence and distant metastasis• Tumor location and size are important

(retroperitoneal tumors are fatal in the majority of cases)

Hyperchromatic, pleomorphic cells with increased mitotic activity and tumor necrosis

Skeletal muscle tumors

Rhabdomyoma

• Benign

• Most frequent primary cardiac tumor of childhood

• Associated with Tuberous Sclerosis

Rhabdomyosarcoma

• Most common soft tissue sarcoma of childhood/adolescence

• Preferred sites: head/neck and genitourinary tract

• Aggressive tumors treated with surgery, chemotherapy and radiation

• Prognosis mostly depends on histologic type and location

• Desmin positive (immunostain)

Rhabdomyosarcoma

• Four histologic types: • Embryonal – most common subtype; includes Botryoid type (best prognosis)

• Botryoid = affects girls <4 years of age (clear, grape-like masses protruding from vagina)

• Alveolar – more aggressive than embryonal type;• t(2;13) PAX3-FOXO1

• t(1;13) PAX7-FOXO1

• Pleomorphic – aggressive

• Spindle Cell/Sclerosing – in children, usually diagnosed at an earlier stage and therefore, the prognosis is usually better

Histologic types of Rhabdomyosarcoma

• Embryonal

• Botryoid

• Spindle Cell

• Alveolar

Pleomorphic

Vascular tumors

Benign Vascular Lesions

• Hemangiomas and Vascular Malformations• Terminology is confusing with many subtypes

Capillary hemangiomaVascular malformation

A few types that are listed in First Aid:• Cavernous hemangioma• cherry hemangioma• capillary hemangioma• strawberry hemangioma

Malignant Vascular Tumor

Angiosarcoma

• Age: peak incidence in 7th decade

• Unknown etiology• Associated with radiation, chronic lymphedema (post mastectomy), synthetic

graft (AV fistula)• First Aid says exposure to vinyl chloride or arsenic (liver angiosarcoma)

• Site: • Scalp (sun exposed skin) of elderly (looks like a bruise)• Any site: retroperitoneum, soft tissues, mediastinum, etc

• Prognosis: Aggressive nearly always fatal malignancy

Angiosarcoma

Infiltrating vascular channels

Highly atypical endothelial cells

Kaposi Sarcoma

• Locally aggressive endothelial tumor that presents with cutaneous lesions in the form of red-purple multiple patches, plaques or nodules

• Can involve different mucosal sites, lymph nodes, and visceral organs

• Associated with HHV8 infection• Human herpes virus 8

Kaposi Sarcoma

• Epidemiology• Classic indolent Kaposi Sarcoma: elderly men of Mediterranean/East

European or Ashkenazi descent• Endemic African Kaposi Sarcoma: middle-aged adults and children in

equatorial Africa who are NOT infected with HIV• Iatrogenic Kaposi Sarcoma: solid organ transplant recipients treated with

immunosuppressive therapy or others taking immunosuppressive meds• AIDS associated Kaposi Sarcoma: most aggressive form of disease

• Treatment: Improve immunosuppression (HAART to control HIV/AIDS), surgery, radiation, chemotherapy, IFN-alpha

• Prognosis: depends on the type and extent of disease

Kaposi Sarcoma

Cutaneous vascular lesion composed of spindle cells, hemorrhage

Gastrointestinal stromal tumor (GIST)

Gastrointestinal Stromal Tumor (GIST)

• Most common primary mesenchymal tumor in the GI tract and spans a clinical spectrum from being benign to malignant

• Interstitial Cells of Cajal – pacemaker cells in the myenteric plexus

• Age: middle aged to older adults

• Sites: gastric (54%), small intestine (32%), colon/rectum (5%), esophagus (1%), and other sites

• Symptoms: Variable; asymptomatic, pain, bleeding, obstruction

Gastrointestinal Stromal Tumor (GIST)

• Prognosis depends on site, size, mitotic rate

• Genetics: KIT oncogenic mutations (c-kit) with constitutive activation of KIT-dependent pathways (80%); others have mutations of PDGFRA

• Treatment: surgery, Gleevec (imatinib) (targeted therapy)

Nerve Sheath Tumors

Schwannoma

• Benign, composed of differentiated neoplastic Schwann cells

• Most are solitary and sporadic (90%)• Bilateral acoustic schwannomas are a/w Neurofibromatosis 2

• Treatment: resection

• Prognosis: benign, does not recur

Schwannoma

• Histology• Antoni A – more compact and cellular

areas

• Antoni B – loose, less cellular areas

• Verocay bodies – palisaded Schwann cell nuclei

Antoni A

Antoni BVerocay bodies

Neurofibroma

• Benign peripheral nerve sheath tumor consisting of differentiated Schwann cells, perineural-like cells, fibroblasts, mast cells, and interspersed• Composed of myelinated and unmyelinated axons

• Majority are sporadic

Neurofibroma

• Neurofibromatosis Type 1 (NF1) NF1 gene on chromosome 17• Diffuse and plexiform neurofibromas• Café-au-lait spots• Axillary or inguinal freckling• Lisch nodules – pigmented iris hamartoma• optic gliomas• pheochromocytomas

• Variants: localized cutaneous, diffuse cutaneous, localized intraneural, plexiform, and massive diffuse soft tissue plexiform tumor

• Lifetime risk for malignant transformation (MPNST) in patients with NF1 may be up to 5-10%

Neurofibroma

Malignant Peripheral Nerve Sheath Tumor (MPNST)• Malignant tumor arising from pre-existing benign nerve sheath tumor

or in a patient with NF1

• Aggressive, poor prognosis

• Diagnosis of exclusion

Malignant Peripheral Nerve Sheath Tumor (MPNST)

Synovial sarcoma

Synovial Sarcoma

• NOT from the synovial membrane (misnomer)

• More common in the lower extremities, around but not within the joints

• Age: teens to young adults

• Sex: more often males

• t(X;18) translocation • 90% have SS18-SSX1 fusion

Synovial Sarcoma

• Monophasic or biphasicpattern• Biphasic shows an admixture of

spindle cells with gland-like structures

• Prognosis: depends on tumor stage at presentation, tumor size, and tumor grade• Adult 5- and 10-year disease

specific survival is 62% and 52%, respectively

Monophasic

Biphasic

Biphasic